Prolactin is a polypeptide hormone, synthesized in and secreted by the adenohypophysis (anterior lobe of the pituitary). Prolactin is synthesized as a precursor protein containing an N-terminal signal peptide and the prolactin sequence. The preliminary amino acid sequence for human prolactin has been reported by Shome, B. and Parlow, A. F., J. Clin. Endocrinol. Metab., 45, 1112 (1977). The preliminary amino acid sequence for the N-terminal signal peptide of rat prolactin has been reported by McKean, D. J. and Maurer, R. A., Biochem., 17, 5215 (1978).
Prolactin was first described as being essential for the initiation of lactation in mammals at parturition. In some species, prolactin has been found to also promote milk secretion. In addition, prolactin also initiates secretion of milk in the hypertophied mammary gland. It has been found that prolactin stimulates the synthesis of milk proteins, such as casein and .alpha.-lactalbumin. Furthermore, prolactin acts synergistically with estrogen to promote mammary gland proliferation. For a general review of the effects of prolactin see Bern, H. A. and Nicoll, C. S., Recent Prog. Horm. Res., 24, 681 (1968). For a review on the effects of prolactin in man, see Frantz, A. G., et al, Rec. Prog. Horm. Res., 28, 527 (1972).
Prolactin also exhibits an anti-gonadotropic hormone action, that is, prolactin inhibits luteinization by luteinizing hormone and inhibits ovulation induced by pregnant mare's serum. Prolactin induces the secretion of progesterone by the newly formed corpus luteum after ovulation. Progesterone itself inhibits ovulation and it has been noted that the antiovulatory action of prolactin depends on the presence of the corpus luteum. It thus appears that the antiovulatory effect of prolactin may be the result of the prolactin-induced progesterone synthesis by the corpus luteum. For a review of prolactin and human reproduction, see Robyn, C., et al., in Human Prolactin, Ed. Pasteels, J. L. and Robyn, C., Americal Elsevier Publishing Co., Inc., New York, p. 167 (1973).
In vitro, prolactin has been found to stimulate glucose uptake and lipogenesis in adipose tissue. When injected, prolactin has been found to mimic a number of actions of growth hormone. Uses of prolactin are based on its known biological activity discussed above. Since prolactin stimulates lactation, it can be administered to insure adequate milk production for breast-feeding mothers. Similarly, rat prolactin, which is very close in amino acid sequence to bovine prolactin, can be administered to dary cows to increase the production of milk. The antiovulatory effect of prolactin can be exploited as a birth control measure by using prolactin as a female contraceptive.
Basic techniques for cloning DNA sequences are now known. For example, Seeburg, P. H. et al, Nature, 270, 486 (1977) describes the cloning of the rat growth hormone gene; Shine, J., et al, Nature, 270, 494 (1977) describes the cloning of the human chorionic somatomammotropin gene; and Derynck, R., et al, Nature, 285, 542 (1980) describes the cloning of the human fibroblast interferon gene.
Methods for the expression of heterologous DNA in a microorganism are now known. In principle, the heterologous DNA coding sequence is inserted in a DNA transfer vector at a point located within an expressible operon. This may result in the production of the desired protein either as such or as a hybrid protein. In the latter case, the inserted sequence must be in reading frame phase with the coding sequence of the operon, and oriented in the same direction with respect to translation. When the conditions are met, translation of the operon results in "read-through" to the inserted coding sequence such that the protein produced is a fusion protein comprising an N-terminal amino acid sequence coded by the expressible operon, followed by an amino acid sequence coded by the insert. See Polisky, B., et al, Proc. Nat. Acad. Sci. USA, 73, 3900 (1976); Itakura, K., et al, Science, 198, 1056 (1977). Several expressible operons have been employed, including those for .beta.-galactosidase, .beta.-lactamase and tryptophan.
Abbreviations used herein are those abbreviations commonly accepted and used by one of ordinary skill in the art. For example, these abbreviations are acceptable by the J. Biol. Chem. without further elucidation.